Author
Information
Rashmi Khadkikar*, Anuya
Pawde**, Neha Saxena***, A. R. Chauhan****
(*
Assistant Professor, ** Fourth Year Resident, *** Third Year Resident, ****
Additional Professor. Department of Obstetrics and Gynecology, Seth GS Medical
College and KEM Hospital ,
Mumbai , India
Abstract
Ovarian
hyperstimulation syndrome (OHSS) is an iatrogenic complication following the
use of clomiphene citrate and gonadotropins for ovulation induction and ovarian
stimulation in assisted reproductive technology. It is characterized by
multicystic ovarian enlargement and fluid displacement from intravascular to
extravascular compartment due to increased capillary permeability; in its
severe form it can be potentially life-threatening, requiring intensive care.
Serum human chorionic gonadotropin (hCG), either exogenous or endogenous, is
the triggering factor and the action is mediated through vascular endothelial
growth factor.[1] We report a case of moderate OHSS following the
indiscriminate use of clomiphene and gonadotropins for ovulation induction in a
patient with polycystic ovarian disease. She was managed conservatively,
conceived but pregnancy was terminated due to fetal malformation.
Introduction
The
incidence of OHSS is approximately 0.3 to 5% amongst women undergoing in vitro
fertilization (IVF) or intrauterine insemination (IUI).[1] Risk
factors include young age, low body weight; higher doses of exogenous
gonadotropins, rapidly rising serum estradiol levels and previous episode of
OHSS. Women with PCOS have a higher incidence of OHSS after gonadotropin
therapy owing to a high number of follicles recruited. OHSS usually resolves
spontaneously over several days, but can last longer especially in conception
cycles.
Mild,
moderate and severe forms are described; in mild OHSS, only ovarian enlargement
is present on ultrasonography (USG), while in moderate form, there is ascites
with mild abdominal distension. Severe form, characterized by hemoconcentration,
thrombosis, oliguria, pleural effusion, and rarely pericardial effusion and
respiratory distress, is seen in only 0.5% patients. Hepatorenal failure, acute respiratory
distress syndrome (ARDS), thromboembolism and even death can occur as
complications.[2]
Case Report
A 29 year old woman, married for 5 years, a case of primary
infertility, was referred to us on day 26 of a treatment cycle, with complaints
of gradually increasing abdominal pain, distension and vomiting since 12 days, and
ultrasonography showing features of OHSS. She had received ovulation induction
for infertility in a private nursing home with tablet clomiphene citrate 100 mg
qd from 3rd to 7th day of menses along with human menopausal gonadotropin (HMG)
75 IU intramuscularly on days 5, 6, 7, 8 and 9. Folliculometry began on day 10 and
showed 8 follicles in right ovary and 7 in left ovary, which reached size of 17-
18 mm on day 15 in both the ovaries; subsequently 4 follicles in right and 3 follicles
in left ovary ruptured on Day 22. Serum estradiol was not estimated. The
patient had vomiting and abdominal pain from day 14 with gradually increasing
abdominal distension which became evident on day 20 of the cycle. On day 22, ascites
was noted on ultrasonography suggestive of OHSS, at which time she was referred.
However she presented on day 26. Baseline hemoglobin was 13 g%, INR was 1.27, bilirubin
was 1.05 mg%, creatinine was 1.4 mg% and electrolytes were normal. Ultrasonography
showed bilateral moderately enlarged ovaries with hemorrhagic follicles with moderate
ascites and bilateral mild pleural effusion.
Figure 1 Multiple follicles and ascites.
The patient was managed conservatively: adequate hydration
in the form of intravenous normal saline and 5% dextrose, supplementation of
multivitamins and potassium chloride, and intravenous paracetamol infusion for
analgesia were given. Her weight, abdominal girth, vital parameters, fluid
intake and urine output, serum electrolytes and coagulation profile were
monitored daily. Electrolytes remained normal; INR decreased to 1.0 within 2
days. Liver and renal function tests were repeated every third day; bilirubin
remained normal and creatinine fell to 1.0 mg%. She was observed for
breathlessness, increment in the abdominal girth or any coagulation abnormality.
Pleural effusion was mild hence did not require thoracocentesis. Her symptoms
reduced over a period of 8 to 10 days; abdominal distension, pain and vomiting
all subsided.
Ten days after admission (day 36 of the cycle), as patient
was amenorrheic, βhCG level was done which was 1687 mIU/ml, this doubled within
48 hours (4945 mIU/ml). USG showed a small gestation sac; hence supportive
treatment with natural micronized progesterone was started and patient was
discharged after 14 days of admission and advised to follow up regularly. A
live pregnancy was noted on ultrasonography at 7 weeks with persistent mild
ascites and bilateral pleural effusion. Unfortunately, at 12 weeks a large
cystic hygroma was noted on ultrasonography and dual marker showed increased
risk of chromosomal anomaly. Patient was counseled for CVS (chorionic villous
sampling) but she opted for medical termination of pregnancy.
Figure 2. Cystic Hygroma.
Discussion
Exact
etiology of OHSS is not known. However vascular endothelial growth factor
(VEGF) is an important causative factor, believed to increase capillary
permeability leading to accumulation of fluid in extravascular compartment.
βhCG has a stimulatory effect on VEGF activity. Antagonizing VEGF action by
dopamine agonist, cabergoline is effective to overcome the changes induced by
gonadotropins.[3] Other vasoactive substances like cytokines
(interleukins IL-2, IL-6, and IL-8), tumor necrosis factor-alpha (TNF-α), and
the ovarian renin-angiotensin system are also implicated.
OHSS can
be classified as early and late onset. Early onset is mainly gonadotropin
related and late onset usually corresponds to presence of hCG in pregnancy.
Early onset OHSS is usually associated with preclinical miscarriage leading to
lower pregnancy rates. Pregnancy may increase the severity of OHSS and prolong
the recovery time. Pregnancy with OHSS is associated with pregnancy
complications such as preeclampsia and gestational diabetes mellitus.
Risk of OHSS can be judged by indicators of
ovarian response like high levels of Anti Mullerian Hormone (AMH), antral
follicular count, absolute value of estradiol or its rate of increase,
increased level of inhibin, none of which were done in our case.
Mild forms can be managed on outpatient
basis with analgesics and counseling about signs of progressive disease,
however moderate and severe forms require admission. The primary aims of
management are correction of hypovolemia, electrolyte imbalance and oliguria.
Hematocrit, renal and liver function tests, electrolytes, coagulation profile,
chest x-ray, abdominal ultrasound for ascites and ovarian volume should be
done. Paracentesis of ascitic fluid, thoracocentesis of pleural fluid, and
heparin may be necessary in case of severe OHSS.
Prevention strategies can be primary or
secondary. In primary prevention, the stimulation protocol is individualized
after classifying patients as poor, normal, or high responders. Primary
strategies include reducing exposure to gonadotropins either by reducing the
dose or using step-down protocol; or reducing duration of FSH exposure by
delaying its administration till mid or late follicular phase. Other primary
strategies include reducing the dose of hCG for oulation trigger and avoiding
its use for luteal phase support. GnRH agonist and recombinant LH can also be
used instead of gonadotropins to trigger ovulation. Use of GnRH antagonist also
reduces severity of OHSS and need for use of secondary prevention strategies.
Use of insulin sensitizers like Metformin is also believed to be effective.
In case of excessive response to ovarian
stimulation, secondary prevention methods are used which include cancellation,
delay, or modification of the stimulation protocol during that cycle. Secondary
prevention strategies include delaying further gonadotropin stimulation and hCG
administration until estradiol levels plateau or decrease, a technique known as
coasting. Another option in IVF cycles is to allow normal progression till
oocyte pickup, followed by cryopreservation of embryos which may be thawed and
reimplanted later when the patient’s estradiol levels are not elevated. [4]
References
1.
Neulen J, Yan Z,
Raczek S, Weindel K, Keck C, Weich HA, et al. Human chorionic
gonadotropin-dependent expression of vascular endothelial growth factor/vascular
permeability factor in human granulosa cells: importance in ovarian
hyperstimulation syndrome. J Clin Endocrinol Metab 1995;80:1967–1971.
2. Calabrò RS, Gervasi G, Leo A, De Luca R,
Balletta T, Casella C, et al. Neurovascular Complications of Ovarian
Hyperstimulation Syndrome (OHSS): From Pathophysiology to Recent Treatment
Options. Recent Pat Endocr Metab Immune Drug Discov 2014 Jun 6. [Epub ahead of
print]
3.
Naredi N, Talwar P, Sandeep K; VEGF antagonist
for the prevention of ovarian hyperstimulation syndrome: Current status; Med J
Armed Forces India. 2014;70:58-63.
4.
Humaidan P, Quartarolo J, Papanikolaou EG.
Preventing ovarian hyperstimulation syndrome: guidance for the clinician;
Fertil Steril 2010; 94:389–400.
Citation
Khadkikar R, Pawde A, Saxena N, Chauhan
AR. Successful Management Of Ovarian Hyperstimulation
Syndrome. JPGO
2014 Volume 1 Number 7 Available from: http://www.jpgo.org/2014/07/successful-management-of-ovarian.html